111(P-56) 非天然ペプチド光学活性α-アミノホスホン酸重合体の固相合成(ポスター発表の部)
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概要
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A solid-phase synthesis of α-amino phosphonic acid oligomers has been established for the first time. N-Fmoc protected 1-aminoethyl phosphonic acid monomethyl ester was set as a model monomer so that the chain could be elongated in the N→P direction by removal of the temporary Fmoc protecting group followed by dehydrative condensation. Thus, the first monomer was connected to TentaGel-attached Jone's branched allyl linker (TentaGel-NHCO(CH_2)_4CH(OH)CH=CH_2) by use of diisopropylcarbodiimide (DIC) and 1-hydroxy-1,2,4-triazolo[4,5-b]pyridine (HOAt) in the presence of diisopropylethylamine (DIEA). Piperidine treatment released the amino group, which was then quantitatively condensed with the second monomer by DIC/HOAt/DIEA method. Use of other condensation reagents such as HOBt, DPPA, and BOP lead to low yields. Four-time repetition of the process afforded TentaGel-attached hexamer possessing methyl groups as the semi-permanent protection of phosphonic acid moieties. The ^<31>P NMR spectrum showed three characteristic signals at δ 26, 31, and 29 that could be assigned to the P atoms of diester, internal monoester amides, and the terminal one, respectively. The signals were broaden because of the possible 64 diastereomers originated from the seven stereogenic atoms. Quantitative detachment from the solid support was successfully realized by a newly developed catalytic deallylation method using [RuCp(P(C_6H_5)_3)(CH_3CN)_2]PF_6 to give the hexamer (^<31>P NMR δ 19, 32, and 30). The ^<31>P NMR spectra change in the chemical shift and the signal intensity observed in each elongation step as well as detachment process indicated the formation of the hexamer. The NMR behavior was also consistent with that of the liquid phase synthesis. The target molecules have a high potentiality in peptide and nucleotide sciences and future biochemical technology. They are analogues of α-amino acid-based peptide in which a carboxylic group is replaced by a phosphonic function. The tetrahedrally arranged phosphorus atom with an sp^3 hybridization and dibasic acid properties modify the size and shape of the three-dimensional structures as well as the isoelectronic points of the parent α-amino acids, which possess a smaller, flat, monobasic carboxylic function. These differences influence their chemical and biological activities because of their inherent competition with the carboxylic counterpart. The present solid-phase synthesis should form the basis of the research directed toward development of a new biological function in combination with a high throughput screening system.
- 2004-10-01
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関連論文
- 111(P-56) 非天然ペプチド光学活性α-アミノホスホン酸重合体の固相合成(ポスター発表の部)
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